Organic Chemistry of Drug Synthesis. Volume 7

amino group is then protected as itstert-butyl carbamate ( 42 ). Reaction of 42
with iodo sucinimide proceeds to form the 3-iodo derivative ( 43 ).

C 2 H 5 O 2 C

NC

37

+ (H 2 CO) 2 HC Br

NaOC 2 H 5

38

C 2 H 5 O 2 C

NC

39

H 2 N

NH 2 NH HN

H 2 N N

O

NH 2

CH(CH 3 O) 2

CH(CH 3 O) 2

40

HCl

HN

H 2 N N

O

41

NH

HN tBuCOCl

tBuCOHN N

O

42

NH

NIS

NIS = N-iodosuccinimide

HN

tBuCOHN N

O

NH

43

I

The key step in this synthesis comprises grafting the benzenzamido-
glutamate moiety found in folic acid onto the heterocycle. Thus, conden-
sation of the iodo-substituted ( 43 ) with acetylide ( 44 ) catalyzed by
tetrakis-triphenylphosphine palladium affords the coupling product ( 45 ).
The triple bond is then converted to the saturated bridge by catalytic
hydrogenation. Saponification then removes the protecting group and at
the same time hydrolyzes the esters on the glutamate fragment to afford 46.^7

NH

O

CO 2 CH 3

44

+ 43

NH

O

CO 2 CH 3

Pd(Ph 3 P) 4

HN

tBuCOHN N

O

NH

45

1. H 2

HN

H 2 N N

O

NH

46

HN

O

CO 2 H

2. NaOH

CO 2 CH 3

CO 2 CH 3

CO 2 H

N

N N

N N

NH 2

H 2 N

NH

O

CO 2 H

CO 2 H

CH 3

Methotrexate

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